Phenyl benzoic acid compounds

ABSTRACT

The invention relates to substituted 5-(phenyl)benzoic acids, esters and non-toxic pharmaceutically accepted salts thereof and processes for their preparation. The substituted 5(phenyl)benzoic acids are useful as anti-inflammatory compounds.

United States Patent 1 1 Ruyle et al. 1 *Jan. 30, 1973 [S4] PHENYLBENZOIC ACID COMPOUNDS 424/258, 424/287, 424/308, 424/311, 424/315424/316 424/317 424/324 [75] Inventors. William V. Ruyle, Scotch Plams,

L s H. S t Alex- I] and" Matzuk Comma, an of [58] Field of Search..260/473 R, 473 S, 520 NJ. [56] References Cited [73] Assigneez Merck &Co., Inc., Rahway, NJ. Notice: The portion of the term of this UMTEDSTATES PATENTS patent su s q nt to ug- 1989, 3,123,531 3/1964 Sahyun..260/473S has been disclaimedv 3,317,382 3/1967 Brunner ..280/520Filed: J 1970 3,249,637 5/1966 Early et al. ..260/559 [21] Appl. No.:44,865 Primary Examiner-Lorraine A. Weinberger Assistant Examiner-JohnF. Terapane Related Application Data Alt0rney-Michael C. Sudol, Jr., H.E. Westlake, Jr. [63] Continuation-in-part of Ser. No. 699,022, Jan. 19,and 1. Louis Wolk 1968, abandoned, which is a continuation-in-part ofS81. N0. 577,819, Sept. 8, 1966, abandoned, which is acontinuation-impart of Ser. No. 420,823, Dec. 23, 1964, abandoned. Theinvention relates to substituted 5-(phenyl)benzoic acids, esters andnon-toxic pharmaceutically accepted 260/268 260/287 salts thereof andprocesses for their preparation. The

260/448 B, 260/473 R, 260/479 R, 260/501 .12, 260/501.l5, 260/50l.l7,260/520, 260/546, 260/559 S, 260/598, 260/612 R, 260/620, 260/646,424/250,

substituted 5-(phenyl)benzoic acids are'useful as antiinflammatorycompounds.

11 Claims, N0 Drawings PHENYL BENZOIC ACID COMPOUNDS CROSS REFERENCES TORELATED APPLICATIONS 1966, now abandoned, which latter case is itself acon- 1 tinuation-in-part of application U.S. Ser. No. 420,823 filed Dec.23, 1964, now abandoned.

BACKGROUND OF INVENTION 1. Field of Invention Generally, this inventionrelates to substituted 5- (phenyl) benzoic acids, esters and non-toxicpharmaceutically acceptable salts thereof for use in the treatment ofinflammatory type diseases. It is an object of this invention to preparecompounds having anti-inflammatory properties but not having many of theside effects which are generally associated with steroid typeanti-inflammatory agents. Prior to this time, steroid typeanti-inflammatory agents such as CORTONE, HYDROCORTONE and DECADRON werecommonly used to relieve inflammation but as stated, these compoundsexhibit many undesirable side effects.

2. Description of the Prior Art The closest prior art compounds whichcould be found are those shown and described in U. S. Pat. Nos.2,744,916 and 3,123,543. Neither of these patents disclose ananti-inflammatory use for the compounds. These references discloseZ-hydroXy-S-phenyl benzoic acid (S-phenyl salicylic'acid) and variousester and amide derivatives thereof. Also the prior art discloses acetylsalicylic acid (aspirin). The compounds of the instant invention,however, are more potent than the prior art compounds at lower dosagesand exhibit fewer side effects than the prior art compounds. The priorart compounds disclosed in the two patent references are not substitutedwith halo or halo groups on the phenyl moiety attached to the 5-positionof the benzoic acid.

SUMMARY OF THE INVENTION AND DESCRIPTION OF THE PREFERRED EMBODIMENTSThis invention relates to new biphenyl compounds, and to a method oftreating inflammation using these compounds and to processes forproducing the same. More specifically, this invention relates tosubstituted 5-(phenyl)benzoic acids, esters, amides, anhydrides andnontoxic pharmaceutically acceptable salts thereof. Still morespecifically, this invention relates to compounds having the generalformula:

wherein X(l5) is halo, such as fluoro or chloro but especially fluoro; Xbeing on one or more of the phenyl carbon atoms;

R is selected from the group consisting of hydroxy, phenoxy,diloweralkylamino, (such as,

dimethylamine), diloweralkylamino loweralkoxy (such asdiethylaminoethoxy);

R is selected from the group consisting of hydrogen and lower alkanoyl(such as acetyl, propionyl and y R is selected from the group consistingof hydrogen and methyl.

Also included in the compounds of this invention are thepharmaceutically non-toxic salts of the acids of the compounds ofFormula I such as the ammonium, alkali metal (such as sodium orpotassium); alkaline earth metals (such as calcium, barium ormagnesium); amine; aluminum; iron; choline; glucosamine; S-methylmethonine salts, piperazine, diloweralkylamino lower alkanol,chloroquine and hydroxy chloroquine; the anhydride of said acids, themixed anhydrides of said acids and 2-acetoxy benzoic acid.

In the especially preferred aspects of this invention,

R is hydroxy,

R is hydrogen or acetyl,

R is hydrogen and X is fluoro;

X being on any position of the phenyl moiety when X is one fluoro groupbut particularly on the 4-position and on any one or combination of theother positions of the phenyl moiety when X represents 2-5 fluorogroups.

Representative compounds of this invention are as follows:

2-hydroxy-5-(4'-fluorophenyl)benzoic acid;

2-acetoxy-5-(4-fluorophenyl)benzoic acid;

2-hydroxy-5-(2-fluorophenyl)benzoic acid;2-hydroxy-5-(2',4'-difluorophenyl)benzoic acid;2-hydroxy-5-(3'-fluorophenyl)benzoic acid;

Z-hydroxy-S-pentafluorophenyl benzoic acid;

2-hydroxy-3-methyl-5-(4'-fluorophenyl)benzoic acid;

2-hydroxy-5-(4-chlorophenyl)benzoic acid;

N,N-dimethyl-5-(4'-fluorophenyl)salicylamide;

B-diethylaminoethyl-5-(4'-fluorophenyl)salicylate;

phenyl-5-(4'-fluorophenyl)salicylate;

aluminum-2-acetoxy-5-(4'-fluorophenyl)-benzoate salt;

aluminum-Z-hydroxy-S-(4'-fluorophenyl)-benzoate salt; I

choline- 2-acetoxy-5-(4'-fluorophenyl)-benzoate salt;

choline-2-hydroxy-5-(4'-fluorophenyl)-benzoate salt;

sodium-2-acetoxy-5-(4'-fluorophenyl)-benzoate salt;

sodium-2-hydroxy-5-(4'-fluorophenyl)-benzoate salt;

2hydroxy-5-(pentafluorophenyl)-benzoic acid;

2-acetoxy-5-(pentafluorophenyl)-benzoic acid;

B-diethylaminoethyI-Z-hydroxy-S-(4'-fluorophenyl)- benzoate;

v B-diethylaminoethyl-Z-acetoxy-5-(4'-fluorophenyl)- benzoate.

This invention also relates to a method of treating inflammation inpatients using a compound of Formula I, particularly an especiallypreferred compound as the active constituent.

We have found that the compounds of Formula I have anti-inflammatoryactivity and are-effective in the prevention and inhibition of edema andgranuloma tissue formation as shown by reduction of edema in the ratsfoot induced by the injection of an inflammatory (phlogistic) agent intothe rats foot.

The compounds of the instant invention can be used to treat inflammationby reducing inflammation and relieving pain in such diseases asrheumatoid arthritis, osteoarthritis, gout, infectious arthritis andrheumatic fever. Furthermore, the compounds of the instant inventionhave better potency at the same dosage levels than similar typecompounds known in the prior art and exhibit a lower incidence of sideeffects.

The compounds of Formula I also have antipyretic and analgesic activityand would be administered and used in the same manner and in the samedosage ranges as if they were being used to treat inflammation asdiscussed further on.

The especially preferred compounds of the instant invention exhibit inaddition to potent anti-inflammatory effects a smaller incidence ofvomiting (emesis effect) than do similar type compounds of the priorart, especially acetyl salicylic acid (aspirin) type compounds. Theespecially preferred compounds of the inagar, pectin, cab-o-sil, andacacia. Exemplary of liquid carriers are peanut oil, olive oil, sesameoil and water. Similarly, the carrier or diluent may include a timedelay material such as glyceryl monostearate or glyceryl distearatealone or with a wax.

Several pharmaceutical forms of the therapeutically useful compositionscan be used. For example, if a solid carrier is used, the compositionsmay take the form of tablets, capsules, powders, troches or lozenges,prepared by standard pharmaceutical techniques. If a liquid carrier isused, the preparation may be in the form of a soft gelatin capsule, asyrup or a liquid supsension.

The active-compounds of Formula I and of the compositions of thisinvention are present in an amount sufficient to treat inflammation,that is to reduce inflammation. Advantageously, the composition willcontain the active ingredient, namely, the compounds of Formula I in anamount of from about 1 mg. to 140 mg. per kg. body weight per day mg. to10 g. per patient per day), preferably from about 2 mg. to 70 mg. perkg. body weight per day (100 mg. to 5 g. per patient per day).

The method of treatment of this invention comprises internallyadministering to a patient (animal or human),a compound of Formula I,particularly an especially preferred compound admixed with a non-toxicpharmaceutical carrier such as exemplified above. The compounds ofFormula I and particularly the especially preferred compounds will bepresent in an amount of from 1 mg. to 140 mg./kg. body weight per day,preferably from about 2 mg. to about mg. per kilogram body weight perday and especially from 4 mg. to 10 mg./kg. body weight per day. Themost rapid and effective anti-inflammatory effect is obtained from oraladministration of a daily dosage of from about 4 to 10 mg./kg./day. Itshould be understood, however, that although preferred dosage ranges aregiven, the dose level for any particular patient depends upon theactivity of the specific compound employed. Also many other factors thatmodify the actions of drugs will be taken into account by those skilledin the art in the therapeutic use of medicinal agents, particularlythose of Formula I, for example, age, body weight, sex, time ofadministration, route of administration, rate of excretion, drugcombination, reaction sensitivities and severity of the'particulardisease.

The test method by which anti-inflammatory activity is determined is bythe ability of the compounds of Formula l to inhibit the edema inducedby injection of an inflammatory (phlogistic) agent into the tissue ofthe foot of the rat. Groups of six male rats (Sprague Dawley strain, 15015 g.) each are given orally the compounds to be tested one hour before0.1 ml. of 1 percent suspension of carragenin is injected into theplantar surface of the right hind paw. Immediately and again three hourslater, the foot volume is measured by its displacement of mercuryandreco'rded automatically. The difference between the immersion andfinal volumes is a measurement of the edema produced. The compoundstested were suspended or dissolved in 0.5 percent methocel whereascontrols received only the methocel. A usual test of 30 mg./kg. and onerepetition plus one dose of mg./kg. were usually given.

The above test method is known to correlate with anti-inflammatoryactivity in humans and is a standard test used to determineanti-inflammatory activity. This correlation is shown by compounds knownto be clinically active, including, INDOClN, ASPIRIN, BU- TAZOLIDIN,TANDEARIL, CORTONE, HYDROCORTONE and DECADRON. The test results for thecompounds shown in Formula I above are compared with similar tests runon the closest of the prior art compounds which applicants coulddetermine, namely, 5-phenyl salicylic acid and the correspondingderivatives thereof disclosed in Sayhun et al. U. S. Pat. No. 2,744,916and 3,123,543 and acetyl salicylic acid (aspirin). The results of thesetests are as follows:

Dose Edema Applicants Compounds mg/kg I: Inhibition2-hydroxy-5-(4-fluorophenyl) 3 .33 18 benzoic acid i0 47 90 772-acetoxy-5-(4'-fluorophenyl) 3.33 25 benzoic acid 10 37 Average 90 70.5 tests 2-hydroxy-5-(2'-fluoropheny l0 33 benzoic acid 30 56 90 692-hydroxy-5-(2',4'-difluoro- 3.33 24 phenyDbenzoic acid 10 51 Average 9077 2 tests 2-hydroxy-5-(3'-fluorophenyl) 10 28 benzoic acid 30 52Z-hydroxy-S-pentafluoro- 10 47 phenyl benzoic acid 30 56 90 682-hydroxy-3-methyl-5-(4'- fluorophenyl)benzoic acid 30 412-hydroxy-5-(4'-chlorophenyl 10 I3 Average benzoic acid 30 27 of 100 52tests N,N-dimethyl-2-hydroxy'5- (4'-fluorophenyl)benzamide 30 23B-diethylaminoethyl -2-hydroxyl l9 5-(4'-fluorophenyl)benzoate 30 35phenyl-Z-hydroxy-S- 4-fluoro- 29 phenyl)benzoate 30 54 Dose Edema PriorArt Compounds mg/kg Inhibmon 5phenyl salicylic acid or2-hydroxy-5(phenyl 50 42 }Average benzoic acid 100 51 of 5 tests 3.33 l09 30 21 90 79 N,N-dimethyl5-phenyl 50 7 }Average salicylamide 100 17 of3 200 27 tests phenyl-S-phenyl salicylate 50 1 1 Average testsB-diethylaminoethyl-S- 50 7 Average phenyl salicylate Hcl 100 29 of 2tests acetyl salicylic acid 3.33 16 Avg. 2 tests (aspirin) (2-acetoxybenzoic acid 30 21 Avg. 5 tests 90 39 Avg. 4 tests 180 60 Avg. 3tests 270 74 Avg. 3 tests In each instance above, the activity of thecompounds shown in Formula I was greatly enchanced by the presence of ahalo group, particularly the fluoro group in the prime phenyl moiety ofthe compound. In one pair, namely 2-hydroxy-5-phenyl salicylic acid (2-hydroxy-S-phenyl benzoic acid) and 2-hydroxy-5-(4- fiuorophenyl) benzoicacid, a statistical analysis was made on the data on edema volumeobtained as previously shown. It was determined that 2-hydroxy-5-(4'-fluorophenyl)benzoic acid is 4.15 times as potent as 2- hydroxy-S-phenylbenzoic acid of the prior art. Statistical data showed that if this testwere repeated, the compound, 2-hydroxy-5-(4-fluorophenyl)benzoic acid,of Formula I would be at least 3.11 times as potent in reducinginflammation as the 2-hydroxy-5-phenyl benzoic acid of the prior art,but not 5.62 times as potent. Also in the above comparisons and from theabove data, 2-hydroxy-5-phenyl benzoic acid when given at a dose of 90mg./kg. approximately matches the effect of2-hydroxy-5-(4-fluorophenyl)benzoic acid at less than one-third thedose. In other words, the addition of fluorine at least tripled thepotency in this particular compound. Generally, it can be seen that thecompounds of the instant invention are more potent at lower dosageranges than compounds of the prior art.

In addition to the above tests, the potency of three of applicantscompounds relative to the best prior art compound, namely, S-phenylsalicylic acid, was estimated recently in the rat foot-edema test aspart of a multiple assay. Three graded doses of each preparation wereadministered orally to individual groups of 6 rats.

All rats were given an intraplantar injection of carrageenan (0.1 ml.ofa 1 percent suspension in the right hind paw) approximately 1 hourafter receiving the test preparations. Three hours later, the volume ofthe edematous foot was measured using a mercury displacement technique.This test method is similar to the one previously described.

The assay was replicated four times since one of the experimentalobjectives was to study day to day variability among relative potencyestimates. For 2-acetoxy- 5-(4'-fluorophenyl)benzoic acid, the fourestimates of relative potency varied from 4.97 to 8.13, a ratio of 1.6for highest to lowest. 2-Hydroxy-5-(4'-fluorophenyl) benzoic acid variedfrom 5.20 to 8.56, a ratio of 1.6, as for2-acetoxy-5-(4'-fluorophenyl)benzoic acid. However, these did not differsignificantly from a ratio of 10, indicating that the estimates werehomogeneous within the limits of experimental error; On the other hand,2-hydroxy-5-pentafluorophenyl benzoic acid varied from 3.05 to 7.25, aratio of 2.4. This indicated significant heterogeneity among theestimates at P 0.05.

Table I below shows average foot volume for each of the preparations.The estimates of relative potency and 95 percent confidence limits(estimated using Dunnetts t) are summarized in Table II, also includedbelow. The combined estimate of relative (i.e., replications 1-4) isalso shown in this table. All replicates showed valid results (i.e.,linearity and parallelism) except replicate 4, which showed a lack ofparallellism at P 0.05. However, since this was not observed in any ofthe other replicates, the apparent lack of parallelism was ignored andaverage relative potencies calculated. Since g was small (varying from0.035 to 0.067), the data were combined using the weighted proceduresuggested by Bliss (Vitamin Methods II, Academic Press Inc., Publishers,New York, 1951, pp. 576-582). The replicate variance was added to theintrinsic variance of the assays for Z-hydroxy-S-pentafluorophenylbenzoic acid. (g is defined in Finney, D. J. Statistical Method inBiological Assay. p. 17, 28, 34, 114 and other pages. Hafar Publ. Co.,New York, 2nd Ed., 1964.)

TABLE I Average Foot Volumes Volume (ml. of mercury displaced)Preparation DoseRep. 1 Rep. 2 Rep. 3 Rep. 4 Z-hydroxy-S- (phenyl) 100.55 0.74 0.60 0.68 benzoic acid 30 0.41 0.54 0.56 0.58 0.24 0.36 0.290.26 2-acetoxy-5-(4'- fluoro- 3.3 0.48 0.65 0.52 0.53 pheny1)benzoicacid 10 0.36 0.47 0.44 0.36 30 0.18 0.25 0.28 0.20 2-hydroxy-5-(4-fluoro- 3.3 0.43 0.61 0.48 0.56 phenyl)benzoic acid 10 0.39 0.40 0.380.43 30 0 I8 0.27 0.22 0.25 2-hydr0xy-5- penta- 3.3 0.38 0.76 0.50 0.58fluorophenyl benzoic 10 0.34 0.50 0.36 0.44 acid 30 0.21 0.37 0.29 0.38

TABLE II Potency and confidence Limits of 2-acetoxy-5-(4 '-fluorophenyl)benzoic acid, 2-hydroxy-5-(4- fluorophenyl)benzoic acid, and2-hydroxy-5- pentafluorophenyl benzoic acid; Relative to 2-hydroxy-5-(phenyl)benzoic acid The compounds of this invention may be preparedeither from a biphenyl phenol or from the following type startingmaterial:

A is an alkali metal ion; and

X and R are as previously defined.

Some of these compounds are prepared from the individual phenyl moietiesof the above starting material by the well-known Gomberg reaction.Others, where the biphenyl moiety is known, require the appropriatereactions to obtain the functional group, if needed, as well as themetal salts. However, all of the compounds may be obtained by firstpreparing an aniline compound containing an X followed by a Gombergreaction with nitrobenzene or anisole or an R (methyl) substitutednitrobenzene or anisole, subsequently reacting either the nitro group orthe methoxy group (from nitrobenzene or anisole) of the biphenylcompound thus prepared so as to obtain the alkali salt startingmaterial. For example, 2-fluoro-5-nitroaniline may be diazotized to thecorresponding 2-fluoro-5- nitrophenol and said nitrophenol reduced toobtain the appropriate aniline compound needed for the Gomberg reaction.(When as in this cited example, the benzene compound contains an alkoxygroup the Gomberg reaction is carried out with nitrobenzene.) Thenitrobiphenyl compound thus obtained may be readily reduced to the aminocompound and subsequently diazotized to the corresponding hydroxycompound. Alternatively, when the aniline compound used in the Gombergreaction does not have an alkoxy substituent onit, it may be reactedwith an alkoxy benzene rather than nitrobenzene. Using this procedure,the alkoxy biphenyl compound obtained after the'Gomberg reaction may, byone step, be converted to the corresponding hydroxy-biphenyl compound,for example by reac- In the Gomberg reaction mentioned above, a mixtureof isomers of the biphenyl compound is obtained; therefore, in order toobtain the desired 4-(substituted phenyl)-benzene compound in a pureform a chromatographic separation is required.

The 4-(substituted phenyl)-phenol compounds obtained as described abovemay then be converted to the corresponding alkali salt by any well-knownmeans, for example, reaction with an appropriate alkali metal in aninert solvent.

The acid compounds of this invention may be prepared from the previouslyprepared alkali-phenolate or phenol compound. The preparation of theseacid compounds are carried out by using the well-known Kolbe-Schmidtcarbonation procedure. In this carbonation step, the phenolate isreacted with carbon dioxide or the phenol is reacted with carbon dioxidein the presence of an alkali carbonate. The process may be shown asfollows:

Xu-s) R u-s) R n-n O OH Equivalents: As previously indicated. Reactionsand Conditions Step (1) Reaction with carbon dioxide at elevatedtemperatures (above C. preferably above C.) with or without a solventpreferably without a solvent (or if the solvent is used, anyhigh-boiling inert solvent may be used) until the reaction issubstantially complete; and subsequent acidification of the reactionmixture. Step (2) Reaction with carbon dioxide in the presence of analkali carbonate, such as potassium, 1 sodium, and the like, especiallypotassium, at elevated temperatures (above 75C. preferably above 100C.)with or without a solvent preferably without a solvent (or if thesolvent is used, any

high boiling inert solvent may be used) until the I reaction issubstantially complete; and subsequent acidification of the reactionmixture.

Reaction steps (1) and (2) are the well-known Kjolbe-Schmidt reaction.Since the reaction conditions are not critical, this inventioncontemplates not only the particular procedure shown but all othervariations of this carbonation step which are well-known in the art.

Thecompounds of this invention, wherein R is a group such that an esteris the final compound, (i.e., R, phenoxy or diethylaminoethoxy), may beprepared by any esterification procedure, using an esterifying agentcontaining the appropriate R group. For example, the benzoic acidcompound of this invention may be reacted with the appropriatehydroxylic compound at elevated temperatures in the presence of a strongacid to form the desired R compound. In the case of compounds where R isphenyl, a mixture of the acid, phenol and phosphorous oxychloride isheated to produce the desired product. In the case wherein R isdiethylaminoethoxy, the potassium salt of the acid is reacted withdiethylaminoethylchloride to produce the desired ester.

The compounds of this invention, wherein R is a group such that an amideis the final compound (i.e., R is dimethylamino), may be prepared by anysuitable amidation reaction. For example, the benzoic acid compound(preferably the methyl or ethyl ester) may be reacted with an aminecompound, at any suitable temperature (room temperature to reflux).

The final compound, wherein R is lower alkanoyl (preferably acetyl), maybe prepared by any suitable alkanoylation reaction. For example, thecorresponding hydroxy benzoic acid, ester, or amide (preferably theester) may be reacted with a lower alkanoic acid anhydride (preferablyacetic anhydride) in the presence of a catalyst such as sulfuric acid,pyridine, ptoluenesulfonic acid, and the like (preferably pyridine), atany suitable temperature (room tempera ture to elevated temperatures)preferably at elevated temperatures to form the desired R compound.

The salts of the final acid compounds of this invention may be preparedby any of the well-known methathesis procedures. For example, thebenzoic acid compound may be reacted with an inorganic base, such assodium hydroxide, potassium hydroxide, ammonium hydroxide, bariumhydroxide, and the like. The anhydrides of this invention may beprepared by any of the well-known procedures in the art.

The preparation of these compounds containing the R and R groups otherthan hydrogen may be prepared in any order. The R group could be placedon the molecule followed by addition of the R substituent or by firstobtaining the R compound followed by addition of the R, group. The orderof these reactions is not critical; they can be run in any desiredfashion.

The following examples are used by way of illustration:

EXAMPLE 1 4-(4-Fluorophenyl )aniline A solution of 3 grams4'-fluoro-4-nitrobiphenyl in 125 ml. methanol is reduced by hydrogen atroom temperature and 40 p.s.i. pressure using 100 mg. platinum oxidecatalyst. After the required uptake of hydrogen, the mixture isfiltered, 50 ml. 2.5 N hydrochloric acid added and the resultingsolution is evaporated in vacuo. After washing the residue with ether,it is dissolved in methanol, filtered and diluted with excess ether. Theprecipitate which is 4-(4-fluorophenyl)aniline hydrochloride is filteredwashed with ether and dried in vacuo at room temperature.

EXAMPLE 2 2 ',3 ',4,5 ,6-Pentafluoro-4-nitrobiphenyl A mixture of 7.5grams of pentafluoroaniline, 200 ml. of nitrobenzene, and 9.0 grams ofiso-amyl nitrite, is warmed on the steam bath until a vigorous reactionwith evolution of gas sets in. This evolution is allowed to proceedwithout heating until it has subsided, and

the mixture is then heated on the steam bath for an additional 3 hours.The excess of nitrobenzene is removed in vacuo. The residue is purifiedfor the desired isomer by elution from a silica gel column usingpetroleumbenzene to yield 2',3',4',5',6'4- nitrobiphenyl.

When 2-fluoroaniline is used in place of pentafluoroaniline in the aboveexample, there is obtained 2-fluoro-4-nitrobiphenyl.

' When 2-nitrotoluene is used in place of nitrobenzene in the aboveexample, there is obtained the corresponding 3-methyl biphenyls.

When 4-fluoroaniline and 2-methyl-nitrobenzene are used in the aboveexample in place of pentafluroaniline and nitrobenzene, there isobtained 4'-fluoro-3-methyl- 4-nitrobiphenyl.

EXAMPLE 3 4-(pentafluorophenyl)aniline A mixture of 5 grams of2',3',4,5',6'4- nitrobiphenyl in 250 ml. of ethanol is reduced byhydrogen at atmospheric pressure and at room temperature using 5 percentpalladium-on-charcoal (0.5 gram) catalyst. After the required uptake ofhydrogen, the mixture is filtered and the catalyst washed with freshethanol. The ethanol solution is then concentrated in vacuo, and theresidue recrystallized from aqueous ethanol to yield4-(pentafluorophenyl)- aniline.

When 2-fluoro-4-nitrobiphenyl is used in place of2',3'D',5,64-nitrobiphenyl in the above examples, there is obtained4-(4-fluorophenyl)- aniline.

I Similarly, when 4-fluoro-3-methyl-4-nitrobiphenyl obtained fromExample 2 is used in place of 2',3',4', 5, 6-pentafluoro-4-nitrobiphenyl in the above example, there is obtained2-methyl-4-(4'-fluorophenyl)- aniline.

EXAMPLE 4 4-(3 '-Chloro -4-fluorophenyl)-anisole A mixture of 8.0 gramsof 3-chloro-4-fluoroaniline, 200 ml. of anisole, and 9.0 grams ofiso-amylnitrite, is warmed on a steam bath until a vigorous reactionwith evolution of gas sets in. This evolution is allowed to proceedwithout heating until it has subsided, and the mixture is then heated onthe steam bath for an additional 3 hours. The excess anisole is removedin vacuo, and the residue is chromatographed on a silica gel columnusing petroleum-benzene as eluent to yield 4-(3'-chloro-4'-fluorophenyl)-anisole.

When 2-chloro-4-fluoroaniline, 2,4-difluoroaniline and 3-fluoroanilineare used in place of 3-chloro-4- fluoroaniline in the above example,there are obtained the corresponding 4-(2'-chloro-4'-fluorophenyl)-anisole, 4-(2',4'-difluorophenyl)-anisole and 4-(3'-fluorophenyl)-anisole.

When 2-methylanisole is used in place of anisole in2-methyl-4-(substituted phenyl)anisole.

EXAMPLE To a solution of 2.1 grams of 4-(3-chloro-4-fluorophenyD-anisole in 50 ml. of boiling acetic acid is added 5 ml. ofhydriodic acid and die boiling continued for 3 hours. Water is added andthe reaction mixture cooled and the 4-(3'-chloro-4'-fluorophenyl)-phenolcrystallizes. Further purification is then achieved by recrystallizationof the solid from aqueous ethanol to yield 4-( 3'-chloro-4-fluorophenyl)-phenol.

When 4-(2-chloro-4'-fluorophenyl)-anisole, 4-(2,4'-difluoropheny1)-anisole and 4-(3'-fluorophenyl)- anisole obtained fromExample 4 are used in place of 4- (3'-chloro-4'fluorophenyl)-anisole inthe above example, there are obtained the corresponding 4-(2-ch1oro-4'-fluorophenyl)-phenol, 4-(2,4-difluorophenyl)- phenol and 4-( 3-fluorophenyl)-phenol.

When the 2- or 3-a1kylphenyl-aniso1e compounds obtained from Example 4above are used in place of 4- (3 -chloro-4'-fluorophenyl)-anisole in theabove example, there is obtained the corresponding 4-(substitutedphenyl)-2-methyl phenol compound.

EXAMPLE 6 4-(4'-Fluorophenyl)-phenol A solution of 32.66 grams of4-(4'-fluorophenyl)- aniline in 120 ml. of glacial acetic acid is cooledto -l 2C. To this solution is added slowly a solution of 12.25 grams ofsodium nitrite in 120 ml. of water with stirring and continued cooling;Five minutes after this addition, the suspension of the diazoniumacetate is added slowly to a boiling solution of 100 ml. of concentratedsulfuric acid and 200. ml. of water. After the final addition of thediazonium salt, the suspension is boiled for an additional 5 minutes andthen allowed to cool to room temperature. The reaction mixture is thenfiltered and the cake dried in vacuo to yield 4-(4- fluorophenyl)phenol, (m .p. 2161C. 24.07 grams).

. When 4-( 2 -fluorophenyl )-anilin e, 4-( pentafluorophenyl)-anilineobtained from Example 3 are EXAMPLE 72-Hydroxy-5-(4'-fluorophenyl)-benzoic acid A mixture of 10 grams of4-(4'-fluorophenyl)-phenol and 27.2 grams of potassium carbonate isexposed to carbon dioxide at 1,300 psi. and 175C. The dark mass obtainedfrom this carbonation is then dissolved in 300 ml. of water and 200 ml.of methylene chloride and the two layers separated. The water layer isthen extracted with ml. of methylene chloride and then acidified with2.5 N hydrochloric acid. This mixture is then filtered and the cakedried in vacuo to yield 5.32 grams of the crude product. The crudeproduct is then recrystallized from benzene-methanol to yield 2.7 gramsof material (m.p. 200204C.). An additional crystallization of thissemi-pure material from benzenemethanol yields analytically pure2hydroxy- 5-(4- fluorophenyD-benzoic acid (m.p. 199-203C.).

When 4-(3'-chloro4-fluorophenyl)-phenol, 4-(2'- chloro-4-fluorophenyl)-phenol, 4-( 2 ,4'-difluorophenyl)-phenol and 4-(3-fluorophenyl)-phenolobtained from Example 5 and 4'-(2'-fluorophenyl)-phenol and4-(pentafluorophenyl)-phenol obtained from Example 6 are used in placeof 4-(4-fluorophenyl)-phenol in the above example, there are obtainedthe corresponding 2hydroxy-5-(3 -chloro-4'-fluorophenyl)-benzoic acid,2- h dr 6xy-5-)2,4:difluorophenyD-be nzoic acid (m.p. 2102l 1C2-hydroxy-5-( 3 -fluorophenyl)-benzoic acid (m.p. l96-197C),2-hydroxy-5-(2-fluorophenyl)-benzoic acid (m.p. 2Ql- -203C.) and2-hydroxy-5- (pentafluorophehim-benzoic acid (m.p. 24 1 243C.).

When the 4-(substituted phenyl)-2-methyl phenol compounds of Examples 5or 6 are used in place of 4- (4'-fluorophenyl)-phenol in the above,there are obtained 2-hydroxy-3-methy1-5-(3'-chloro-4-fluorophenyl)-benzoic acid and 2-hydroxy-4-methyl-5-(2'-chloro-4'-fiuorophenyl)-benzoic acid, respectively.

Similarly, when 2-methyl-4-(4'-fluorophenyl)- phenol obtained fromExample 6 is used in place of 4- (4'-fluorophenyl)-phenol in the aboveexample, there benzoic acid.

EXAMPLE 8 Sodium-2-hydroxy-5-(4 -fluorophenyl )-benzoate A mixture of0.1 mole of 2-hydroxy,-5-(4- fluoropheny1)-benzoic acid and 0.1 mole ofsodium hydroxide in 100 ml. of water is stirred at room temperature forone-half hour. The reaction mixture is then concentrated in vacuo toyield sodium-2-hydroxy- 5-(4-fluorophenyl)-benzoate.

- When the benzoic acid compounds obtained from Example 7 are used inplace of the 2-hydroxy-5-(4- fluorophenyl)-benzoic acid in the aboveexample, there are obtained the corresponding sodium salts.

Similarly, when choline, glucosamine, S-methylmethionine, potassiumhydroxide, ammonium hydroxide, barium hydroxide, calcium hydroxide,piperazine, chloroquine, hydroxychloroquine, dimethylaminoethanoL'andmagnesium hydroxide, are used in place of sodium hydroxide in the aboveexample, there are obtained the corresponding choline, glucosamine,S-methyl-methionine, potassium, ammonium, barium, calcium, piperazine,chloroquine, hydroxychloroquine, dimethylaminoethanol and magnesiumsalts, respectively.

EXAMPLE 9 A. Methy1-2-hydroxy-5-(4-fluorophenyl)-benzoate A solution of5.0 grams of 2-hydroxy-5 (4' fluorophenyl)-benzoic acid in 20 ml. ofmethanol and 2 ml. of concentrated sulfuric acid is heated at reflux forhours. The mixture is then cooled and partitioned between (751150 ml.)water and ethyl acetate and the organic layer washed with dilute sodiumbicarbonate solution. The organic layer is then dried over magnesiumsulfate and concentrated in vacuo to yield 5.3 grams (as an oil) ofmethyl-2-hydroxy-5-(4'- fluorophenyl)-benzoate.

When the benzoic acid compounds obtained from Example 7 are used inplace of 2-hydroxy-5-(4- fluorophenyl)-benzoic acid in the aboveexample, there are obtained the corresponding methyl esters.

Similarly, when ethanol and n-butanol are used in place of methanol inthe above example, there are obtained the corresponding ethyl andn-butyl esters.

B. Phenyl-2-hydroxy-5-(4'-fluorophenyl)-benzoate A mixture of 6.4 gramsof 2-hydroxy-5-(4'- fluorophenyl)benzoic acid, 2.8 grams of phenol and1.7 grams of phosphorous oxychloride is heated at 1 14C. until no morehydrogen chloride is evolved. The reaction mixture is cooled to roomtemperature and filtered. The resulting solid material is digested indilute sodium carbonate solution, filtered, washed with water, dried andrecrystallized from isopropyl alcohol to yield 4.0 grams of phenyl2-hydroxy-5-(4-fluorophenyl)benzoate, m.p. 808 1C.

Following the above procedure but using an equivalent amount of2-acetoxy-5-(4'-fluorophenyl)benzoic acid in place of 2-hydroxy-5-(4'-fluorophenyl)benzoic acid, there is obtained phenyl 2-acetoxy-5-(4-fluorophenyl) benzoate.

C. B-Diethylaminoethyl-2-hydroxy-5-(4'- fluorophenyl)-benzoatehydrochloride A mixture of 4.0 grams (0.0175 mole) of 2-hydroxy-5-(4-fluorophenyl)benzoic acid, 2.4 grams of potassium carbonate in 50ml. of isopropanol is refluxed for one-half hr. 3.0 Grams (0.0175 In.)of B- diethylaminoethylchloride.Hcl. is added and the mixture refluxedwith stirring for hours. The reaction mixture is then distributedbetween water and ethyl ether. The ether layer is then washed withwater, dried and evaporated to a small volume. Dry hydrogen chloride gasis then passed into the ether solution and the resulting precipitate isfiltered and recrystallized from acetone/ethyl ether to yieldB-diethylaminoethyl- 2-hydroxy-5-(4-fluorophenyl)-benzoatehydrochloride.

EXAMPLE 10 N,N-Dimethyl-2-hydroxy-5-( 4'-fluorophenyl benzamide Amixture of 5.3 grams of methyl-2-hydroxy-5-(4- fluorophenyl)-benzoateand ml. of dimethylamine is reacted in a bomb at 100C. for 4 hours.After cooling, the bomb is opened and the excess dimethylamine removed.The residue is then recrystallized from benzene to yieldN,N-dimethyl-2-hydroxy-5-(4'- fluorophenyl)-benzamide which has amelting point of 166l68C.

When the benzoic acid methyl esters obtained from Example 9 are used inplace of methyl-2-hydroxy-5-(4 '-fluorophenyl)-benzoate in the aboveexample, there are obtained the corresponding N,N-dimethyl-benzamidecompounds.

EXAMPLE 1 1 2-Acetoxy-5-(4'-fluorophenyl)-benzoic acid A solution of 3.0grams of 2-hydroxy-5-(4'- fluorophenyl)-benzoic acid in 12 ml. ofpyridine and 8 ml. of acetic anhydride is heated on a steam bath for 20minutes. The mixture is then poured onto ice and the product extractedwith methylene chloride. The methylene chloride solution is dried andthen evaporated. The residue is recrystallized from benzene to yield2-acetoxy-5-(4'-fluorophenyl)-benzoic acid (m.p. 134-l37C.).

When the 2-hydroxy-benzoic acid compounds obtained from Example 7 areused in place of 2-hydroxy- 5-(4'-fluorophenyl)-benzoic acid in theabove example, there are obtained the corresponding 2-acetoxybenzoicacid compounds.

Similarly, when propionic acid anhydride is used in place of aceticanhydride, the corresponding 2- propionoxy compound is obtained.

EXAMPLE l2 Anhydride of 2-acetoxy-4-(4'-fluorophenyl)-benzoic acid Asolution of 0.01 mole of 2-acetoxy-4-(4- fluorophenyl)-benzoic acid and0.01 mole of thionyl chloride in 30 ml. of dry benzene is warmed untilthe formation of the substituted benzoyl chloride is complete. Theresulting solution is concentrated to one-half volume in vacuo and isadded to a solution of 0.01 mole of 2-acetoxy-4-(4-fluorophenyl)-benzoicacid and 0.01 mole of pyridine in 30 ml. of benzene. The mixture isstirred at room temperature overnight, filtered, and the filtrate washedwith cold dilute sodium bicarbonate solution. After drying and removalof benzene, the product is recrystallized from benzenehexane.

Alternatively, the anhydride may be formed by reacting for5 hours atroom temperature 0.02 mole of 2- acetoxy-4-(4-f1uorophenyl)-benzoic acidand 0.01 mole of dicyclohexylcarbodiimide in 20 parts oftetrahydrofuran, followed by filtration and concentra tion of thefiltrate to yield the anhydride.

When a solution of 2-acetoxy benzoic acid in pyridine is used in placeof the 2-acetoxy-4-(4'- fluorophenyl)-benzoic acid pyridine solution inthe above example, there is obtained the mixed anhydride of2-acetoxy-4-(4-fiuorophenyl)-benzoic acid and 2- acetoxy benzoic acid.

EXAMPLE 13 5-(4-F1uorophenyl)-2-hydroxy-3-methyl-benzoic acid A.4-(4'-Fluorophenyl)-2-hydroxymethyl-phenol A solution of 5.0 g. ofmethyl-2-hydroxy-5-(4'- fluorophenyl)-benzoate in 25 ml. of ether isadded to a stirred suspension of 1.28 g. of lithium aluminum hydride inml. of ether at a rate sufficient to maintain gentle reflux. Heating atreflux temperature is continued for 0.5 hour after the addition. Theexcess hydride is decomposed with ethyl acetate, and sufficient dilutehydrochloric acid is added to make separation of the ether layerpossible. The ether phase is washed with water, dried over magnesiumsulfate, and concentrated to dryness. Trituration with hexane yielded3.93 g. of 4-(4'-fluorophenyl)-2-hydroxymethylphenol, m.p. l-l57C.Recrystallization from aqueous ethanol furnished pure material, m.p. 1 157C. B. 4-(4'-Fluorophenyl)-2-acetoxymethylphenyl acetate A mixture of3.0 g. of 4-(4-fluorophenyl)-2-hydroxymethyl-phenol, 10 ml. of aceticanhydride, and 6 ml. of pyridine is heated on the steam bath for onehour. The reaction mixture is poured into ice water, stirred for 0.5hour, and the product extracted into ether. After drying withmagnesium-sulfate and treating with activated charcoal,4-(4'-fluorophenyl)-acetoxymethylphenyl acetate is obtained as an oil.The yield is 3.95 g. C. 4-(4'-Fluorophenyl)-2-methylpheny1 acetate Asolution of 3.9 g. of 4-(4-fluorophenyl)-2-acetoxymethylphenyl acetatein 30 ml. of glacial acetic acid is hydrogenated at 40 p.s.i. and C.until the uptake of hydrogen is one equivalent. The catalyst and solventare removed, the product is taken up in ether, washed with dilute sodiumbicarbonate solution, dried, and the solution concentrated to dryness.The crude yield is 2.95 g. Chromatography of 2.6 g. of the crude,product on g. of silica gel furnishes 2.1 g. of pure 4-(4'-fluorophenyl)-2-methylphenyl acetate, eluted with benzene, r n.p. 7173C.D. 4-(4@Fluorophenyl)-2-methyl-phenol A mixture of 2.01 g. of4-(4-fluorophenyl)-2- methylphenyl acetate, 10 ml. of ethanol, and 10ml. of

1.25 N sodium hydroxide is heated at reflux for 20 minutes. The reactionmixture is concentrated to dryness in vacuo, and the residue redissolvedin water. After acidification and extraction of the product with ether,1.6 g. of 4-(4-fluorophenyl)-2-methyl-phenol is obtained, m.p. -l31C. vE. 5-(4'-Fluorophenyl)-2-hydroxy-3-methyl-benzoic acid A mixture of 1.5g. of 4-(4-fluorophenyl)-2-methylphenol and 6 g. of anhydrous potassiumcarbonate is heated in a-bomb at 175C. and 850 p.s.i. carbon dioxidepressure for 16 hours. The reaction mixture is suspended in hot water,acidified, and the cooled mixture extracted with ethyl acetate. Theethyl acetate was extracted repeatedly with portions of 1 percentsolution of sodium bicarbonate. The pooled bicarbonate extracts areacidified, and the product extracted into ether. After treatment withmagnesium sulfate and activated charcoal, the ether solution wasconcentrated to a small volume. The addition of hexane cause thecrystallization of 0.71 g. of 5-(4-fluorophenyl)-2-hydroxy-3-methyl-benzoic acid, mp. 21 l-213C. (sublimes).

. When the 3-unsubstituted ester compounds of Example 9 are used inplace of methyl-2-hydroxy-5-(4- fluorophenyl)-b enzoate in the aboveexample, there are obtained the corresponding 3-methyl benzoic acidcompounds.

EXAMPLE 14 A dry filled capsule was prepared from the followingcomponents:

magnesium stearate benzoic acid 300 mg. corn starch mg. Cab-o-sil 5 mg.Sterotex 15 mg.

A dry filled capsule can be prepared by using the following compounds asactive ingredients instead of 2- acetoxy-5-(4'-fluorophenyl)-benzoicacid:

2-hydroxy-5-(4'-fluorophenyl)-benzoic acid;

2-acetoxy-5-( 2 ,4'difluorophenyl )-benzoic acid;2-hydroxy-3-methyl-5-(4'-fluorophenyl)-benzoic acid;

phenyl-5-(4' -fluorophenyl )-2-hydroxy benzoate;

2-hydroxy-5-( 3 -fluorophenyl )-benzoic acid; or any other preferredcompounds as shown in the specification.

1f capsules of lower potency are to be made, the capsule size could bereduced or the quantity of corn starch could be increased.

EXAMPLE 1 5 Compressed tablets were prepared with the followingcomponents:

2-acetoxy-5-(4'-fluorophenyl)- benzoic acid 300 mg. cornstarch 30 mg.polyvinylpyrrolidone 10 mg.

(I) -Rl or apharmaceutically acceptable non-toxic salt thereof wherein Xis fluoro;

R is hydroxy, phenoxy, and;

R is hydrogen or lower alkanoyl;

R is hydrogen. 2. A compound of the formula:

o0oH

or a pharmaceutically acceptable non-toxic salt thereof wherein R ishydrogen or lower alkanoyl.

3. The compound of claim 2 which is 2-hydroxy-5- (pentafluorophenyl)benzoic acid. 1

4. The compound of claim 2 which is 2-hydroxy-5-(2 '-fluorophenyl)-benzoic acid.

5. The compound of claim 2 which is 2-hydroxy-5-(3'-fluorophenyl)-benzoic acid.

6. The compound of claim 2 which is 2-hydroxy-5-(2,4-difluorophenyl)-benzoic acid.

7. A compound of the formula:

or a pharmaceutically acceptable non-toxic salt thereof

1. A compound of the formula:
 2. A compound of the formula:
 3. Thecompound of claim 2 which is 2-hydroxy-5-(pentafluorophenyl) benzoicacid.
 4. The compound of claim 2 which is2-hydroxy-5-(2''-fluorophenyl)-benzoic acid.
 5. The compound of claim 2which is 2-hydroxy-5-(3''-fluorophenyl)-benzoic acid.
 6. The compound ofclaim 2 which is 2-hydroxy-5-(2'',4''-difluorophenyl)-benzoic acid.
 7. Acompound of the formula: or a pharmaceutically acceptable non-toxic saltthereof wherein R2 is hydrogen or acetyl.
 8. The compound of claim 7which is 2-hydroxy-5-(4''-fluorophenyl)benzoic acid.
 9. The compound ofclaim 7 which is 2-acetoxy-5-(4''-fluorophenyl)benzoic acid.
 10. Thecompound of claim 7 wherein R2 is hydrogen and the pharmaceuticallyacceptable non-toxic salt is the choline salt of the acid.